AGC1-malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway.
J Neurochem
; 124(3): 347-62, 2013 Feb.
Article
en En
| MEDLINE
| ID: mdl-23216354
ABSTRACT
The mitochondrial transporter of aspartate-glutamate Aralar/AGC1 is a regulatory component of the malate-aspartate shuttle. Aralar deficiency in mouse and human causes a shutdown of brain shuttle activity and global cerebral hypomyelination. A lack of neurofilament-labeled processes is detected in the cerebral cortex, but whether different types of neurons are differentially affected by Aralar deficiency is still unknown. We have now found that Aralar-knockout (Aralar-KO) post-natal mice show hyperactivity, anxiety-like behavior, and hyperreactivity with a decrease of dopamine (DA) in terminal-rich regions. The striatum is the brain region most affected in terms of size, amino acid and monoamine content. We find a decline in vesicular monoamine transporter-2 (VMAT2) levels associated with increased DA metabolism through MAO activity (DOPAC/DA ratio) in Aralar-KO striatum. However, no decrease in DA or in the number of nigral tyrosine hydroxylase-positive cells was detected in Aralar-KO brainstem. Adult Aralar-hemizygous mice presented also increased DOPAC/DA ratio in striatum and enhanced sensitivity to amphetamine. Our results suggest that Aralar deficiency causes a fall in GSH/GSSG ratio and VMAT2 in striatum that might be related to a failure to produce mitochondrial NADH and to an increase of reactive oxygen species (ROS) in the cytosol. The results indicate that the nigrostriatal dopaminergic system is a target of Aralar deficiency.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Trastornos Psicomotores
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Sustancia Negra
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Dopamina
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Ácido Aspártico
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Cuerpo Estriado
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Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias
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Enfermedades Mitocondriales
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Proteínas de Transporte de Membrana Mitocondrial
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Malatos
Idioma:
En
Revista:
J Neurochem
Año:
2013
Tipo del documento:
Article
País de afiliación:
España